Lactonamycin was isolated by Matsumoto and coworkers in 1996 from Streptomyces rishiriensis in a screen for new antibiotics active against drug resistant bacterial strains. Lactonamycin exhibits potent antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE). Structurally related polyketides including the tetracenomycins and elloramycin display potent antitumor activity. The goals of this research program are as follows: 1) Development of general synthetic methods to access lactonamycin, elloramycin, saintopin E, and the numerous tetracenomycin structures. In particular the construction of the ABCD-ring systems through a strategy of tandem 1,4-addition-Dieckmann ring closure will provide access to the natural product targets as well as analogs. 2) Construct advanced synthetic intermediates postulated as biosynthetic precursors of lactonamycin as part of elucidating the biosynthetic pathway to lactonamycin. 3) Construct an appropriate form of the carbohydrate L-rhodinose for completion of a chemical synthesis of lactonamycin. 4) Expand and define the scope of the tandem 1,4-addition-Dieckmann ring closure for applications to related type II polyketide natural products. Further expansion of the methodology to the synthesis of condensed polycyclic heterocycles. 5) Expand the [3+2] cycloaddition reaction of quinones with nitrile oxides to gain access to diverse type II polyketide structures such as DNA helicase inhibitor heliquinomycin.